tbuckley/cabot-search huggingface dataset:
Efficacy and Safety of Dapagliflozin by Baseline Insulin Regimen and Dose: Post Hoc Analyses From DECLARE-TIMI 58
Authors: Rena Pollack, Itamar Raz, Stephen D. Wiviott, Erica L. Goodrich, Sabina A. Murphy, Ilan Yanuv, Aliza Rozenberg, Ofri Mosenzon, Anna Maria Langkilde, Ingrid A.M. Gause-Nilsson, Deepak L. Bhatt, Lawrence A. Leiter, Darren K. McGuire, John P.H. Wilding, Marc S. Sabatine, Avivit Cahn
Journal: Diabetes Care (2022)

OBJECTIVE The cardiorenal benefits of adding sodium–glucose cotransporter 2 (SGLT2) inhibitor therapy for patients on insulin, particularly those on intensive regimens that include short-acting (SA) insulin, have not been explored. RESEARCH DESIGN AND METHODS In Dapagliflozin Effect on Cardiovascular Events trial (DECLARE-TIMI 58), 17,160 patients with type 2 diabetes were randomized to dapagliflozin or placebo for a median follow-up of 4.2 years. Cardiovascular (CV), renal, metabolic, and safety outcomes with dapagliflozin versus placebo by insulin dose and regimen were studied with Cox regression models. RESULTS The study included 7,013 insulin users at baseline, with 4,650 (66.3%) patients on regimens including SA insulin. Insulin doses varied, with 2,443 (34.8%) patients receiving &amp;lt;0.5 IU/kg, 2,795 (39.9%) 0.5 to ≤1 IU/kg, and 1,339 (19.1%) &amp;gt;1 IU/kg. Dapagliflozin reduced CV death/hospitalization for heart failure among overall insulin users (hazard ratio [HR] 0.82 [95% CI 0.69–0.97]) and consistently in patients on insulin regimens with or without SA insulin (0.83 [0.67–1.03] and 0.78 [0.57–1.07], respectively, Pinteraction = 0.75). No heterogeneity was observed by insulin dose (Pinteraction = 0.43). The HR for major adverse CV events with dapagliflozin among insulin users (0.84 [0.74–0.97]) was similar irrespective of regimen or dose (Pinteraction = 0.75 and 0.07). Dapagliflozin reduced the rate of adverse renal outcomes overall and consistently across subgroups of insulin users. Decreases in HbA1c, weight, and systolic blood pressure with dapagliflozin were seen regardless of insulin dose or regimen. The known safety profile of dapagliflozin was unchanged in patients on intensive insulin regimens. CONCLUSIONS The benefits and safety of dapagliflozin were maintained in high-risk patients receiving high-dose or intensive insulin regimens including SA insulin.
Effect of a Mobile Health Technology–Based Diabetes Education Program on Glucose Control in Patients With Type 2 Diabetes Initiating Premixed Insulin: A Prospective, Multicenter, Observational Study
Authors: Si Chen, Jingyi Lu, Danfeng Peng, Fengjing Liu, Wei Lu, Wei Zhu, Jian Zhou, Weiping Jia
Journal: Diabetes Care (2022)
The Impact of Carbamylation and Anemia on HbA1c’s Association With Renal Outcomes in Patients With Diabetes and Chronic Kidney Disease
Authors: Mengyao Tang, Anders Berg, Eugene P. Rhee, Andrew S. Allegretti, Sagar Nigwekar, S. Ananth Karumanchi, James P. Lash, Sahir Kalim
Journal: Diabetes Care (2022)

OBJECTIVE Glycated hemoglobin (HbA1c) can predict risk for microvascular complications in patients with diabetes. However, HbA1c’s reliability in chronic kidney disease (CKD) has been questioned, with concerns including competition from another posttranslational protein modification, carbamylation, acting on the same amino groups as glycation, and anemia with reduced erythrocyte lifespans leading to altered glycation accumulation. We investigated whether carbamylation and anemia modify the impact of HbA1c on renal outcomes in patients with diabetes and CKD. RESEARCH DESIGN AND METHODS In 1,516 participants from the Chronic Renal Insufficiency Cohort study with diabetes and CKD, Cox regression models were applied to evaluate the association between HbA1c and CKD progression (composite of end-stage kidney disease or 50% decline in estimated glomerular filtration rate [eGFR]), stratified by carbamylated albumin (C-Alb) quartiles and anemia. RESULTS The mean eGFR was 38.1 mL/min/1.73 m2, mean HbA1c was 7.5% (58 mmol/mol), and median C-Alb was 8.4 mmol/mol. HbA1c was lower in the higher C-Alb quartiles. During a median follow-up of 6.9 years, 763 participants experienced CKD progression. Overall, higher HbA1c was associated with an increased risk of CKD progression (adjusted hazard ratio 1.07 [95% CI 1.02–1.13]). However, using stratified analyses, HbA1c was no longer associated with CKD progression in the highest C-Alb quartile, but did show a monotonic increase in CKD progression risk across each lower C-Alb quartile (P-interaction = 0.022). Anemia also modified the association between HbA1c and CKD progression (P-interaction = 0.025). CONCLUSIONS In patients with coexisting diabetes and CKD, the association between HbA1c and CKD progression is modified by carbamylation and anemia.
Erratum to ‘Incidence rates, emerging serotypes and genotypes, and antimicrobial susceptibility of pneumococcal disease in Taiwan: A multi-center clinical microbiological study after PCV13 implementation’ [Journal of Infection Vol 84, Issue 6 (2022) Pages 788-794]
Authors: Chih-Ho Chen, Rajendra Prasad Janapatla, Lin-Hui Su, Hsin-Chieh Li, Kuang-Che Kuo, Chun-Chih Chien, Chang-Chun Hsiao, Cheng-Hsun Chiu
Journal: Journal of Infection (2022)
Effect of a SARS-CoV-2 booster vaccine dose on the immune response of adults with Down syndrome
Authors: Ayla Yarci-Carrión, Laura Esparcia-Pinedo, Gloria Mateo-Jiménez, Arantzazu Alfranca, Diego Real de Asúa, Ainhoa Gutiérrez-Cobos
Journal: Journal of Infection (2022)
Global and regional estimates of orphans attributed to maternal cancer mortality in 2020
Authors: Florence Guida, Rachel Kidman, Jacques Ferlay, Joachim Schüz, Isabelle Soerjomataram, Benda Kithaka, Ophira Ginsburg, Raymond B. Mailhot Vega, Moses Galukande, Groesbeck Parham, Salvatore Vaccarella, Karen Canfell, Andre M. Ilbawi, Benjamin O. Anderson, Freddie Bray, Isabel dos-Santos-Silva, Valerie McCormack
Journal: Nature Medicine (2022)

Despite women being disproportionally affected by cancer deaths at young ages, there are no global estimates of the resulting maternal orphans, who experience health and education disadvantages throughout their lives. We estimated the number of children who became maternal orphans in 2020 due to their mother dying from cancer in that year, for 185 countries worldwide and by cause of cancer-related death. Female cancer deaths-by country, cancer type and age (derived from GLOBOCAN estimates)-were multiplied by each woman's estimated number of children under the age of 18 years at the time of her death (fertility data were derived from United Nations World Population Prospects for birth cohort), accounting for child mortality and parity-cancer risk associations. Globally, there were 1,047,000 such orphans. Over half of these were orphans due to maternal deaths from breast (258,000, 25%), cervix (210,000, 20%) and upper-gastrointestinal cancers (136,000, 13%), and most occurred in Asia (48%: India 15%, China 10%, rest of Asia 23%) and Africa (35%). Globally, there were 40 new maternal orphans due to cancer per 100,000 children, with a declining trend with a higher Human Development Index (range: 121 in Malawi to 15 in Malta). An estimated 7 million children were prevalent maternal orphans due to cancer in mid-2020. Accelerating the implementation of the World Health Organization's cervical and breast cancer initiatives has the potential to avert not only millions of preventable female cancer deaths but also the associated, often-overlooked, intergenerational consequences of these deaths.
The Protection Conferred by HSD17B13 rs72613567 on Hepatic Fibrosis Is Likely Mediated by Lowering Ballooning and Portal Inflammation
Authors: Eduardo Vilar-Gomez, Tiebing Liang, Katherine Yates, Laura Wilson, Rohit Loomba, Naga Chalasani
Journal: Clinical Gastroenterology and Hepatology (2022)
Molecular and clinical diversity in primary central nervous system lymphoma
Authors: I. Hernández-Verdin, E. Kirasic, K. Wienand, K. Mokhtari, S. Eimer, H. Loiseau, A. Rousseau, J. Paillassa, G. Ahle, F. Lerintiu, E. Uro-Coste, L. Oberic, D. Figarella-Branger, O. Chinot, G. Gauchotte, L. Taillandier, J.-P. Marolleau, M. Polivka, C. Adam, R. Ursu, A. Schmitt, N. Barillot, L. Nichelli, F. Lozano-Sánchez, M.-J. Ibañez-Juliá, M. Peyre, B. Mathon, Y. Abada, F. Charlotte, F. Davi, C. Stewart, A. de Reyniès, S. Choquet, C. Soussain, C. Houillier, B. Chapuy, K. Hoang-Xuan, A. Alentorn
Journal: Annals of Oncology (2022)

Primary central nervous system lymphoma (PCNSL) is a rare and distinct entity within diffuse large B-cell lymphoma presenting with variable response rates probably to underlying molecular heterogeneity.To identify and characterize PCNSL heterogeneity and facilitate clinical translation, we carried out a comprehensive multi-omic analysis [whole-exome sequencing, RNA sequencing (RNA-seq), methylation sequencing, and clinical features] in a discovery cohort of 147 fresh-frozen (FF) immunocompetent PCNSLs and a validation cohort of formalin-fixed, paraffin-embedded (FFPE) 93 PCNSLs with RNA-seq and clinico-radiological data.Consensus clustering of multi-omic data uncovered concordant classification of four robust, non-overlapping, prognostically significant clusters (CS). The CS1 and CS2 groups presented an immune-cold hypermethylated profile but a distinct clinical behavior. The 'immune-hot' CS4 group, enriched with mutations increasing the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and nuclear factor-κB activity, had the most favorable clinical outcome, while the heterogeneous-immune CS3 group had the worse prognosis probably due to its association with meningeal infiltration and enriched HIST1H1E mutations. CS1 was characterized by high Polycomb repressive complex 2 activity and CDKN2A/B loss leading to higher proliferation activity. Integrated analysis on proposed targets suggests potential use of immune checkpoint inhibitors/JAK1 inhibitors for CS4, cyclin D-Cdk4,6 plus phosphoinositide 3-kinase (PI3K) inhibitors for CS1, lenalidomide/demethylating drugs for CS2, and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) inhibitors for CS3. We developed an algorithm to identify the PCNSL subtypes using RNA-seq data from either FFPE or FF tissue.The integration of genome-wide data from multi-omic data revealed four molecular patterns in PCNSL with a distinctive prognostic impact that provides a basis for future clinical stratification and subtype-based targeted interventions.
Managing Waldenström’s macroglobulinemia with BTK inhibitors
Authors: Christian Buske, Wojciech Jurczak, Joe-Elie Salem, Meletios A. Dimopoulos
Journal: Leukemia (2022)

Abstract Bruton’s tyrosine kinase (BTK) inhibition is one of the treatment standards for patients with relapsed/refractory Waldenström’s macroglobulinemia (WM) and for patients with WM who are unsuitable for immunochemotherapy (ICT). It offers deep and durable responses with a manageable safety profile that is generally favorable compared with ICT regimens. However, the limitations of the first approved BTK inhibitor (BTKi), ibrutinib, include reduced efficacy in patients lacking the characteristic WM mutation ( MYD88 L265P ) and toxicities related to off-target activity. The risk of atrial fibrillation (AF) and other cardiovascular side effects are a notable feature of ibrutinib therapy. Several next-generation covalent BTKis with greater selectivity for BTK are at various stages of development. In November 2021, zanubrutinib became the first of these agents to be approved by the European Medicines Agency for the treatment of WM. Head-to-head trial data indicate that it has comparable efficacy to ibrutinib for patients with WM overall, although it may be more effective in patients with CXCR4 mutations or wild-type MYD88 . In the clinical trial setting, its greater selectivity translates into a reduced risk of cardiovascular side effects, including AF. Acalabrutinib, which is pre-approval in WM, appears to offer similar advantages over ibrutinib in terms of its safety profile. Beyond the next-generation covalent BTKis, non-covalent BTKis are an emerging class with the potential to provide a therapeutic option for patients who relapse on covalent BTKis. In the future, BTKis may be increasingly utilized within combination regimens. Several ongoing trials in WM are investigating the potential for BTKi use in combination with established and novel targeted agents.
Targeting cell cycle and apoptosis to overcome chemotherapy resistance in acute myeloid leukemia
Authors: Victoria Y. Ling, Jasmin Straube, William Godfrey, Rohit Haldar, Yashaswini Janardhanan, Leanne Cooper, Claudia Bruedigam, Emily Cooper, Paniz Tavakoli Shirazi, Sebastien Jacquelin, Siok-Keen Tey, Jonathan Baell, Fei Huang, Jianwen Jin, Yichao Zhao, Lars Bullinger, Megan J. Bywater, Steven W. Lane
Journal: Leukemia (2022)
Phase I study of a novel glioblastoma radiation therapy schedule exploiting cell-state plasticity
Authors: Jamie A Dean, Shyam K Tanguturi, Daniel Cagney, Kee-Young Shin, Gilbert Youssef, Ayal Aizer, Rifaquat Rahman, Lubna Hammoudeh, David Reardon, Eudocia Lee, Jorg Dietrich, Kaoru Tamura, Masaru Aoyagi, Lacey Wickersham, Patrick Y Wen, Paul Catalano, Daphne Haas-Kogan, Brian M Alexander, Franziska Michor
Journal: Neuro-Oncology (2022)

Abstract Background Glioblastomas comprise heterogeneous cell populations with dynamic, bidirectional plasticity between treatment-resistant stem-like and treatment-sensitive differentiated states, with treatment influencing this process. However, current treatment protocols do not account for this plasticity. Previously, we generated a mathematical model based on preclinical experiments to describe this process and optimize a radiation therapy fractionation schedule that substantially increased survival relative to standard fractionation in a murine glioblastoma model. Methods We developed statistical models to predict the survival benefit of interventions to glioblastoma patients based on the corresponding survival benefit in the mouse model used in our preclinical study. We applied our mathematical model of glioblastoma radiation response to optimize a radiation therapy fractionation schedule for patients undergoing re-irradiation for glioblastoma and developed a first-in-human trial (NCT03557372) to assess the feasibility and safety of administering our schedule. Results Our statistical modeling predicted that the hazard ratio when comparing our novel radiation schedule with a standard schedule would be 0.74. Our mathematical modeling suggested that a practical, near-optimal schedule for re-irradiation of recurrent glioblastoma patients was 3.96 Gy × 7 (1 fraction/day) followed by 1.0 Gy × 9 (3 fractions/day). Our optimized schedule was successfully administered to 14/14 (100%) patients. Conclusions A novel radiation therapy schedule based on mathematical modeling of cell-state plasticity is feasible and safe to administer to glioblastoma patients.
Image-guided drug delivery in nanosystem-based cancer therapies
Authors: Marjolein I. Priester, Timo L.M. ten Hagen
Journal: Advanced Drug Delivery Reviews (2022)

The past decades have shown significant advancements in the development of solid tumor treatment. For instance, implementation of nanosystems for drug delivery has led to a reduction in side effects and improved delivery to the tumor region. However, clinical translation has faced challenges, as tumor drug levels are still considered to be inadequate. Interdisciplinary research has resulted in the development of more advanced drug delivery systems. These are coined "smart" due to the ability to be followed and actively manipulated in order to have better control over local drug release. Therefore, image-guided drug delivery can be a powerful strategy to improve drug activity at the target site. Being able to visualize the inflow of the administered smart nanosystem within the tumor gives the potential to determine the right moment to apply the facilitator to initiate drug release. Here we provide an overview of available nanosystems, imaging moieties, and imaging techniques. We discuss preclinical application of these smart drug delivery systems, the strength of image-guided drug delivery, and the future of personalized treatment.
The Impact of Genetic Surfing on Neutral Genomic Diversity
Authors: Flávia Schlichta, Antoine Moinet, Stephan Peischl, Laurent Excoffier
Journal: Molecular Biology and Evolution (2022)

Range expansions have been common in the history of most species. Serial founder effects and subsequent population growth at expansion fronts typically lead to a loss of genomic diversity along the expansion axis. A frequent consequence is the phenomenon of "gene surfing," where variants located near the expanding front can reach high frequencies or even fix in newly colonized territories. Although gene surfing events have been characterized thoroughly for a specific locus, their effects on linked genomic regions and the overall patterns of genomic diversity have been little investigated. In this study, we simulated the evolution of whole genomes during several types of 1D and 2D range expansions differing by the extent of migration, founder events, and recombination rates. We focused on the characterization of local dips of diversity, or "troughs," taken as a proxy for surfing events. We find that, for a given recombination rate, once we consider the amount of diversity lost since the beginning of the expansion, it is possible to predict the initial evolution of trough density and their average width irrespective of the expansion condition. Furthermore, when recombination rates vary across the genome, we find that troughs are over-represented in regions of low recombination. Therefore, range expansions can leave local and global genomic signatures often interpreted as evidence of past selective events. Given the generality of our results, they could be used as a null model for species having gone through recent expansions, and thus be helpful to correctly interpret many evolutionary biology studies.
Covid-19: “Grotesque inequity” that only a quarter of paxlovid courses go to poorer countries
Authors: Gareth Iacobucci
Journal: BMJ (2022)

Covid-19: "Grotesque inequity" that only a quarter of paxlovid courses go to poorer countries Gareth IacobucciWealthy nations have secured almost three times as many courses than developing countries of Pfizer's covid-19 oral antiviral drug paxlovid, an analysis by Oxfam and the People's Vaccine Alliance has found.
Extracellular matrix profiles determine risk and prognosis of the squamous cell carcinoma subtype of non-small cell lung carcinoma
Authors: Amelia L. Parker, Elise Bowman, Adriana Zingone, Brid M. Ryan, Wendy A. Cooper, Maija Kohonen-Corish, Curtis C. Harris, Thomas R. Cox
Journal: Genome Medicine (2022)

Squamous cell carcinoma (SqCC) is a subtype of non-small cell lung cancer for which patient prognosis remains poor. The extracellular matrix (ECM) is critical in regulating cell behavior; however, its importance in tumor aggressiveness remains to be comprehensively characterized.Multi-omics data of SqCC human tumor specimens was combined to characterize ECM features associated with initiation and recurrence. Penalized logistic regression was used to define a matrix risk signature for SqCC tumors and its performance across a panel of tumor types and in SqCC premalignant lesions was evaluated. Consensus clustering was used to define prognostic matreotypes for SqCC tumors. Matreotype-specific tumor biology was defined by integration of bulk RNAseq with scRNAseq data, cell type deconvolution, analysis of ligand-receptor interactions and enriched biological pathways, and through cross comparison of matreotype expression profiles with aging and idiopathic pulmonary fibrosis lung profiles.This analysis revealed subtype-specific ECM signatures associated with tumor initiation that were predictive of premalignant progression. We identified an ECM-enriched tumor subtype associated with the poorest prognosis. In silico analysis indicates that matrix remodeling programs differentially activate intracellular signaling in tumor and stromal cells to reinforce matrix remodeling associated with resistance and progression. The matrix subtype with the poorest prognosis resembles ECM remodeling in idiopathic pulmonary fibrosis and may represent a field of cancerization associated with elevated cancer risk.Collectively, this analysis defines matrix-driven features of poor prognosis to inform precision medicine prevention and treatment strategies towards improving SqCC patient outcome.
Surface Engineering of Auxetic Scaffolds for Neural and Vascular Differentiation from Human Pluripotent Stem Cells
Authors: Xingchi Chen, Chang Liu, Matthew Wadsworth, Eric Z. Zeng, Tristan Driscoll, Changchun Zeng, Yan Li
Journal: Advanced Healthcare Materials (2022)

Abstract Auxetic materials are the materials that can display negative Poisson's ratio that describes the degree to which a material contracts (or expands) transversally when axially strained. Human stem cells sense the mechanical properties of the microenvironment, including material surface properties, stiffness, and Poisson's ratio. In this study, six different auxetic polyurethane (PU) foams with different elastic modulus (0.7–1.8 kPa) and Poisson's ratio (−0.1 to −0.5) are used to investigate lineage specification of human induced pluripotent stem cells (hiPSCs). The surfaces of the foams are modified with chitosan or heparin to enhance the adhesion and proliferation of hiPSCs. Then, the vascular and neural differentiation of hiPSCs are investigated on different foams with distinct elastic modulus and Poisson's ratio. With different auxetic foams, cells show differential adherent density and differentiation capacity. Chitosan and heparin surface functionalization promote the hindbrain and hippocampal markers, but not forebrain markers during neural patterning of hiPSCs. Properly surface engineered auxetic scaffolds can also promote vascular differentiation of hiPSCs. This study represents a versatile and multifunctional scaffold fabrication approach and can lead to a suitable system for establishing hiPSC culture models in applications of neurovascular disease modeling and drug screening.